Abstract

Background: Breast cancer (BC) occurs between one in 3000 to one in 10 000 pregnancies. About 20% to 44% of BC diagnosed in women younger than 30 ys is associated by Her2/Neu receptor overexpression. The prognosis of the Her2/Neu positive BC has improved fundamentally with the introduction of trastuzumab. The increasing age of child bearing mothers leads to an increased probability of the incidence of BC, and thus Her2/Neu positive BC in pregnancy as well.

The administration of trastuzumab during pregnancy is not recommended and leads to the development of reversible oligo- and anhydramnios and fetal renal volume. The mechanism has not been identified yet. Trastuzumab is a humanized monoclonal IgG kappa 1 antibody, which is transported across the human placenta. Moreover, the presence of Her2/Neu receptor in the second and third trimester placenta and fetal kidneys has been described. The interaction of trastuzumab with these tissues/receptors may cause the development of oligo- and anhydramnion. Apart of the study that tested the transplacental transfer of trastuzumab in pregnant baboon (2009), to our knowledge there are no data in the literature tested the transfer of trastuzumab across the human placenta.

Objectives: We examined the transfer of Trastuzumab® in a relevant pharmaceutical concentration across the human term placenta with the ex-vivo placenta perfusion model, as well as the expression of the Her2/Neu receptor in the placenta tissue (syncytiotrophoblast).

Methods: The dual ex vivo human placental perfusion model was used to analyse the transfer of Trastuzumab® across the placental barrier (n=3). The ex vivo placenta perfusion model was performed by establishing an artificial maternal and fetal circulation system within 20 minutes after delivery. Nutrition and oxygen supply was established to keep the tissue and its barrier function under physiological conditions over several hours. Closed loops of the maternal and fetal circulations were used within the perfusion experiments. We used an antibody concentration in the maternal circulation of 50 µg/ml. This concentration is a common bolus application in therapy of Her/2positive BC. Quantification of the protein was performed by ELISA. The presence of Her2/Neu in the placenta was determined by immunhistochemical stainings.

Results: The transport of Trastuzumab® in the maternal to fetal direction could not be detected over 90 minutes of placenta perfusion. An average antibody concentration decrease of about 30% was determined in the maternal circulation. The presence of the Her2/Neu receptor in the syncytiotrophoblast layer was detectable by immunhistochemical staining.

Conclusions: The results indicate that Trastuzumab® does not cross the human placenta within 90 min of placenta perfusion. Due to the presence of Her2/Neu receptor expression at the syncytiotrophoblast of the human placenta, a binding to this receptor is assumed. This may explain the trastuzumab decrease over time in maternal circulation. These findings indicate that the pregnancy complications can also be caused by a direct effect of trastuzumab on the human placenta. Our results are in contrast to published data of transplacental transfer of trastuzumab in pregnant baboon published 2009 and need to be investigated in further studies.